Acute ischemic stroke is the leading cause of disability in the United States. Therapeutic strategies to improve functional outcome by stimulating brain's recovery mechanisms hold a great promise for more than 700,000 annual stroke victims. Since brain function is heavily dependent on cerebral blood flow, enhancement of angiogenesis by proangiogenic agents and/or stem cells is being evaluated as a therapeutic modality in experimental models of stroke. Although type 2 diabetes is present in almost 40% of the acute ischemic stroke patients and worsens stroke outcome, how diabetes affects cerebral angiogenesis and neurovascular unit architecture that overall may influence the pathophysiology and magnitude of brain injury and recovery is not known. The objective of this exploratory R21 application is to understand the impact of type 2 diabetes on brain neovascularization and neurovascular patterning before and after stroke. We showed that diabetes stimulates cerebrovascular remodeling/arteriogenesis and ischemic brain injury superimposed on this pathology results in smaller infarcts but greater hemorrhagic transformation (HT) and poor functional outcomes. Our recent exciting data in nondiabetic rats suggested that angiogenic response after ischemic stroke depends on the optimization of redox signaling. Based on these findings, the central hypothesis is that diabetes differentially regulates cerebral angiogenesis before and after stroke in a redox-dependent manner. We will test this hypothesis in 2 specific aims: Aim 1: Determine the effect of diabetes and diabetic stroke on cerebral angiogenesis, and Aim 2: Determine the role of ischemia/reperfusion-generated oxidative stress on angiogenic vascular endothelial growth factor (VEGF) signaling in diabetes. An enhanced understanding of cerebrovascular networking in the setting of diabetes would not only allow us to develop preventive and therapeutic strategies for stroke in high risk patients but also improve therapeutic angiogenesis in stroke. Given that more than 40% of 700,000 annual ischemic stroke patients have a history of diabetes, we believe this project is translational in nature and will have a significant positive impact on human health. PUBLIC HEALTH RELEVANCE: A great majority of stoke patients have diabetes. These patients have severe stroke outcomes. This project will determine the mechanisms of vascular protection before and after stroke under diabetic conditions to develop treatment strategies in these high risk patients.